The present invention relates to amino acid-derived bioerodible polymers and to methods of synthesizing such polymers.
U.S. Pat. No. 4,980,449 describes new polyiminocarbonates useful as degradable polymers in general, and as tissue compatible bioerodible materials for biomedical uses. That application also discloses several new methods for synthesizing polyiminocarbonates. The disclosure of polyiminocarbonates and methods of synthesizing polyiminocarbonates in said U.S. Pat. No. 4,980,449 is hereby incorporated herein by reference thereto.
According to U.S. Pat. No. 4,980,449, polyiminocarbonates are structurally related to polycarbonates. The polyiminocarbonates have imino groups in the places normally occupied by carbonyl oxygen in the polycarbonates. This modification of the polymer backbone imparts a significant degree of hydrolytic instability to the polymer. The hydrolytic instability is desirable because it renders the polymer biodegradable and provides gradual erosion of the polymer within the body when the polyiminocarbonate is used as an implanted medical device. Yet, polyiminocarbonates retain some of the good mechanical properties of corresponding polycarbonates, in particular, mechanical strength.
One preferred species of polyiminocarbonates disclosed by U.S. Pat. No. 4,908,449 has amino acid-based repeating structural units with Formula I: ##STR1## with L.sub.1 being any one of the commonly used N-terminus protecting groups used in peptide synthesis including those disclosed in Bodanszky, The Practice of Peptide Synthesis (Springer-Verlag, New York, 1984), the disclosure of which is herein incorporated by reference thereto; and L.sub.2 being a straight or branched alkyl chain; and Y being hydrogen or a C-terminus protecting group: ##STR2## as also disclosed by Bodanszky, which disclosure is also herein incorporated by reference thereto, with L.sub.3 being an alkyl, aryl or alkylaryl group and preferably a hexyl group. The preferred N-terminus protecting groups were benzyloxycarbonyl and tert-butoxycarbonyl groups.
The above polymers are essentially iminocarbonate-amides with pendent chains attached to the polymer backbone. Such polyiminocarbonates are prepared by reacting an amino acid-derived diphenol with an amino acid-derived dicyanate.
In Kohn, U.S. Pat. No. 4,638,045, poly(amino acid iminocarbonates) are disclosed that possess suitable tissue compatibility and bioerodibility properties for biomedical uses. These polymers, however, are impractical in certain applications because they lack suitable mechanical properties, in particular, ductility. The amino acid-derived polyiminocarbonates of U.S. Pat. No. 4,980,449 were disclosed to possess a higher molecular weight and therefore better mechanical properties.
The drawback to polyiminocarbonates, however, is that the imino group is heat sensitive with thermal decomposition temperatures (T.sub.d) close to the lowest possible processing temperature. The polyiminocarbonates of U.S. Pat. No. 4,980,449 and U.S. Pat. No. 4,638,045 became soft enough for compression molding about 20.degree. to 60.degree. C. above their glass transition temperature T.sub.g, which temperatures are close to or above their T.sub.d, which is determined by the intrinsic properties of the iminocarbonate linkage.
Consequently, the practical applicability of most polyiminocarbonates is limited by the fact that conventional fabrication techniques such as compression molding, extrusion or injection molding cannot be applied without simultaneous decomposition of the polymer. The lack of detailed studies relating the monomer structure to the physicomechanical properties of the corresponding polymer made it difficult to identify more heat stable polyiminocarbonates among the numerous molecular structures claimed in U.S. Pat. Nos. 4,980,449 and 4,638,045.